Introduction of medical devices implanted into the body can lead to serious nosocomial infections. Implanted medical devices (e.g., venous and arterial catheters, neurological prostheses, wound drains, urinary “Foley” catheters, peritoneal catheters, and other lumenal indwelling devices), while sterilized and carefully packaged to guard against introduction of pathogens during implantation, pose a risk during insertion, and subsequently. During insertion bacteria can be picked up from the skin and carried into the insertion site where bacterial colonization may ensue. In the case of urinary and venous catheters, especially those used long term, there is a significant threat of microbial growth along the exterior surface of the catheter. This can lead to chronic urinary tract infections (CUTI), or septicemia in the case of venous and arterial catheters, thrombolytic emboli caused with infections introduced by the catheter, and other life-threatening complications, especially among the elderly. Methods aimed at circumventing this problem have included irrigating the implant site with antibiotic, applying various antibiotic ointments or antibiotic impregnated sponges near the exterior opening by which infection most likely occurs, impregnating the polymer base coating the implant device with antibiotics, or silver, either as a heavy metal or in combination with antibiotics, or treatment of patients systemically with antibiotics. Despite the foregoing attempts at preventing infections associated with the implantation of catheters and lumenal indwelling devices in various body cavities, these methods of preventing and treating infections have not proven satisfactory.
For example, the long term use, and misuse, of antibiotics often results in the selection of antibiotic resistant strains. Hence, in general, systemic antibiotic therapy is ill advised and ineffective in warding off CUTI, for example. The secondary side effects of systemic antibiotic treatments can also pose a serious risk to many patients. Furthermore, in many implant sites, the formation of fibrous tissue around the implant site reduces the supply of blood to the implant cavity thereby precluding systemic antibiotic treatment of the critical space between the implant and capsular endothelial wall. In the case of a urinary catheter (e.g., Foley catheter), antibiotics injected as a coating in the urinary canal may be washed out during drainage through leakage of some urine along the urinary tract outside the catheter, or resorbed before they can achieve sufficient levels to effectively kill bacteria growing within localized regions of the urinary tract.
It can be appreciated from the foregoing problems that there is a pressing need for the development of better methods of preventing and treating infections caused with catheter insertions into body cavities, particularly for the development of methods and devices which circumvent the problem of selecting out antibiotic resistant organisms. The problem is particularly acute since it is known that when catheters, and other indwelling lumenal devices, are inserted into body cavities such as the urinary tract, venous or arterial vessels, a biofilm forms rapidly on the walls of the implant device. Bacteria then propagate free from attack by the body's own phagocytic defense system, and also free from systemic antibiotic treatments (Gristina, A. G., Science 237: 1588-1595 (1987); Zhang, X. et al., Medical Plastics and Biomaterials, November 1997, pp. 16-24).
Free elemental iodine is attractive as an anti-infective agent. There are no known organisms which have developed resistance against its oxidizing activity in attacking critical sulfhydryl groups, and other functional groups in proteins, essential for bacterial survival (Second Asian Pacific Congress on Antisepsis in Postgrad. Med. J. 69 (suppl. 3), 1993: S1-S134; Third Asian Pacific Congress on Antisepsis in Dermatology 195 (suppl. 2), 1997: S1-S120). A few parts per million (ppm) in solution is sufficient to kill bacteria and viruses (LeVeen et al. (1993) Gynecology & Obstetrics 176: 183-190; Barabas, E. S. and Brittain, H. G. (1998) in Analytical Profiles of Drug Substances and Excipients (ed., Brittain, H. G.) Vol. 25, AP, San Diego, pp. 341-462). On the other hand, because of its high degree of diffusion through water, air and lipids, and its reactivity as an oxidizing agent, elemental iodine is difficult to handle in a clinical setting.
Methods of stabilizing iodine in solution illustrated by the formulation, Povidone-iodine, for example, are well known to those in the art. This formulation has been tried without satisfactory success in conferring to catheters anti-infective properties. Povidone-iodine washes free of devices as a coating, and is consequently present an insufficient duration to significantly reduce the incidence of infections brought on following implantation, particularly in complex biological media Jansen et al. (J. Antimicrobial Chemotherapy 30: 135-139 (1992)), and Kristinsson et al. (J. Biomaterials Applications 5: 173-184 (1991)), sought to confer to catheters anti-infective activity by preloading the lumen with iodine complexed with polyvinylpyrrolidone (PVP). While they were able to demonstrate weak anti-infective activity in aqueous buffered solutions, this strategy proved unsatisfactory in complex media Jansen reported that the activity conferred by this technique lasted for less than 3 hours in serum. Indeed, Jansen sought to preload PVP coated catheters with Lugol's solution, a concentrated mixture of inorganic iodine and iodide, in an attempt to enhance the anti-infective activity of the iodine transferred to the catheter lumen. As noted below, and in example 8 illustrating the invention described herein, the use of iodophor complexing agents such as PVP, designed to sequester elemental iodine, works against, rather than promotes, conference of anti-infective activity to catheters. This can be appreciated since iodophors, in binding iodine, compete for iodine, decreasing its rate of egress across the polymer base of the catheter, thus ameliorating the effectiveness of iodine in conferring to catheters anti-infective activity.
Povidone-iodine as it is commercially formulated with a total iodine content of 10,000 ppm also introduces a high iodine exposure level to the patient of which only about 1 ppm is free iodine, the form necessary to affect microbial killing. PVP, the binding agent used in trapping iodine in aqueous solutions in a bound form, is also problematic in retarding wound-healing (LeVeen et al. (1993) Gynecology & Obstetrics 176: 183-190). The short-lived retentions of Povidione-iodine coatings on implant devices, the fact that binding agents such as PVP aggravate wound-healing, and the fact that the free form of iodine in Povidone-iodine at 1 ppm is below the essential ˜2 ppm level of free iodine required for efficient microbial killing, points out the need for a better method of presenting iodine as an anti-infective agent to catheters, and other indwelling implant devices (e.g., wound drains).
Morain and Vistnes (Plastic & Reconstructive Surgery 59: 216-222 (1977)) sought to impregnate silicone discs with elemental iodine by soaking discs in 95% ethanolic solutions in which crystalline iodine had been dissolved, and then tested the discs for anti-infective activity. While they were able to demonstrate the release of anti-infective activity in their iodine impregnated disc samples, they concluded that the use of iodine was “contraindicated” because of concern that it would add to the vinyl group of polymethylvinylsiloxane in the formulations they used, potentially altering “the substance sufficiently that an entirely new set of physiochemical properties might result.” It is also apparent that the method of impregnating an implant using crystalline iodine and an alcoholic solution is impractical in a clinical setting. Iodine crystals in combination with alcohol can cause severe chemical burns if put into direct contact with tissues, it is difficult to control dosing of crystalline iodine in a reliable fashion, and messy working with mixtures of crystalline iodine and alcohol. Thus the practical obstacles of preparing impregnated anti-infective implants using this technology pose serious logistical problems in the handling and release of iodine.
Birnbaum et al. (Plastic & Reconstructive Surgery 69: 956-959 (1982)) sought to confer to silicone breast implants anti-infective activity by injecting Povidone-iodine solutions into the internal cavity of the implants in studying prevention of spherical contractures believed to be caused by inflammation, but found comparable fibrosis, collagen deposition and inflammation to that of control animals implanted with silicone implants lacking anti-infective activity. Birbau et al. taught that in their formulation “the effects of iodine are limited to a proscribed period of time, following which all inhibitory activity is lost.” They concluded that “. . . Bacteria arriving subsequent to this period of activity would not be inhibited. Fibrosis and late scar contracture might then ensue . . .” thus teaching away from the use of delivering free iodine into silicone polymer implants.
LeVeen and LeVeen (U.S. Pat. No. 5,156,164) claimed to have conferred bactericidal activity to a contraceptive sponge by impregnating the polyurethane polymer base comprising the sponge with an aqueous solution of free iodine made up in Lugol's solution. More recently, Shikani and Domb (U.S. Pat. Nos. 5,695,458; 5,762,638) described the fabrication of iodine impregnated polymer coatings of varying thickness prepared by dissolving elemental iodine into organic solvents which also contained organic polymers which were then layered and coated by dipping and drying steps over medical devices including blood handling collection bags, tubes, catheters, and the like. This technology involves multiple layering of iodine impregnated polymers, the spacing of additional layers of polymer lacking iodine dissolved in the organic solvents, and varying such steps aimed at retarding and managing the egress rates of free iodine from the polymer base to provide for a controlled anti-infective activity. Tyagi and Singh (Biomedical Sciences Instrumentation 33: 240-45 (1997)) in a similar fashion sought to confer to latex Foley urinary balloon catheters anti-infective activity by dipping the outer external surfaces of the latex balloon in toluene solutions comprising a mixture of elemental iodine and latex, and then drying and storing catheters treated in this manner at low temperature in polythene bags prior to use, however. Neither the polyurethane nor latex methods are amenable to on site delivery of anti-infective activity to an existing catheter or implant device at the bedside, or in the surgical suite. The use of organic solvents, drying times and multiple dipping steps make these methods impractical in a clinical setting in conferring anti-infective activity to the implant device.
The latter techniques of entrapping elemental iodine within a polymer base as taught by LeVeen and LeVeen, Shikani and Domb, and Tyagi and Singh, rely, in general, on starting with free elemental iodine dissolved within a solvent system, and trapping it within a polymer base, a process wrought with technical difficulties. The layering and drying steps used in the art taught by Shikani and Domb, and Tyagi and Singh, moreover, is costly and time consuming. In addition, none of the methods starting with free elemental iodine address the problem of how to ensure a long shelf life for iodine entrapped within the polymer base of the implant device. Once the device is fabricated and loaded with iodine, it can be appreciated by those knowledgeable in the art that iodine will begin to diffuse into the air because of the inherent chemical properties of iodine to disperse free of its initial site of deposition. Furthermore, the high degree of reactivity of free iodine is a drawback to these methods. It can be anticipated, for example, that iodine will react and become depleted from the device in encountering varying reducing compounds coming into contact with the device. Such compounds capable of depleting the iodine entrapped within the device may be in the form of gases, liquids or solids including the wrapping materials in which the devices are stored. In addition to these limitations, in the art taught by Shikani and Domb, and Tyagi and Singh, the layering of varying polymer layers atop one another using organic solvents in which iodine is dissolved is limited to polymers which are compatible with one another in forming strong and uniform adhesive bonds, and which will not swell or alter shape when wetted and presented to a biological site of treatment. This is contrary to the properties of many medical grade polymers used in medical devices that have a tendency to swell and distort in shape once placed within the body. Polymer swelling and distortion is unacceptable in the art taught by Shikani and Domb since the latter phenomenon results in rupturing of the adhesive bonds between the iodine coated layers of the implant device and loss of control in the release rates of free iodine egressing from the device.
Therefore, there remains a need in the art to mitigate the risk of infection from such medical devices.